Do We Need Biologics in Pediatric Asthma Management?

Transcription

1 Do We Need Biologics in Pediatric Asthma Management? Ting Fan LEUNG, MBChB, MD, FRCPCH, FAAAAI Professor and Chairman Department of Paediatrics The Chinese University of Hong Kong

2 Asthma and Allergy by ISAAC Wong GW, Leung TF, Ko FW. AAIR 2013

3 Levels of Asthma Control Characteristic Controlled (All of the following) Partly controlled (Any present in any week) Uncontrolled Daytime symptoms None (2 or less / week) More than twice / week Limitations of activities None Any Nocturnal symptoms / awakening Need for rescue / reliever treatment None None (2 or less / week) Any More than twice / week 3 or more features of partly controlled asthma present in any week Lung function (PEF or FEV 1 ) Normal < 80% predicted or personal best (if known) on any day Exacerbation None One or more / year 1 in any week

4 Inefficient Asthma Control Worldwide Rabe et al. JACI 2004

5 AIRIAP2 in Asian Children GINA-defined Asthma Control Use of Urgent Healthcare Services Use of Anti-asthma Medications Wong GW et al. Allergy 2013

6 Control-based Asthma Management Cycle Review response: symptoms, exacerbations, side effects, patient satisfaction, spirometry Assess: diagnosis, symptom control and risk factors, spirometry, inhaler technique and adherence, patient preference Adjust treatment: asthma medications, nonpharmacological strategies, treat modifiable factors

7 Assessment of Uncontrolled Asthma Watch patient using the inhaler; discuss adherence and barriers to use Correct errors and recheck frequently Confirm the diagnosis of asthma May repeat spirometry after 2-3 wks of ICS Remove potential risk factors and manage comorbidities Tobacco smoke, allergen exposure, NSAIDs; rhinitis, obesity, depression/anxiety Consider treatment Step-up Balance potential benefits and risks Refer to specialist or severe asthma clinic Refer early if severe asthma despite step 4 treatments for 3-6 mo, or doubts about diagnosis

8 Stepwise Asthma Management Step 1 Step 2 Step 3 Step 4 Step 5 Asthma Education (self monitoring, written action plan, regular review) Treat modifiable factors (tobacco smoke, obesity, anxiety) Advise non-pharmacological strategies (physical activity, weight loss, avoidance of sensitizers) As-needed short-acting 2 -agonist (SABA) As-needed SABA or low-dose ICS/formoterol # Select one Select one Select one Add one or more Add one or both None Low-dose ICS Low-dose ICS plus LABA** Medium/high-dose ICS plus LABA Refer for add-on treatments: Tiotropium*, omalizumab, or mepolizumab* Consider low-dose ICS Leukotriene receptor antagonist (LTRA) Medium/high-dose ICS Add tiotropium* Add low-dose oral corticosteroid Low-dose theophylline* Low-dose ICS plus LTRA (or theophylline*) High-dose ICS plus LTRA (or theophylline*) * Not for children < 12 yrs; ** preferred step 3 treatment is medium-dose ICS for children aged 6-11 yrs; # as maintenance and reliever by SMART approach

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10 No Long-term Effectiveness of ICS Symptomatic relief but no long-term benefit after fluticasone in preschool kids Guilbert et al. New Engl J Med 2006

11 % patients achieving Total Control Total Asthma Control 60 FP 500 FP 250 FP 100 Total Control was achieved at a lower steroid dose with Seretide Seretide 500 Seretide 250 Seretide Steroid naïve (S1) Low dose ICS (S2) Moderate dose ICS (S3) Bateman ED et al. AJRCCM 2004

12 Precision Medicine: From Treating Phenotypes to Endotyping to Genotyping CLINICAL PHENOTYPE ENDOTYPE (mechanisms or pathways) GENOTYPE E.g. severe asthma, early vs late onset, atopic, fixed airflow obstruction E.g. eosinophilic asthma, Th2-type, high IgE

13 Molecular Phenotyping for Severe Asthma Severe Asthma Exacerbations Symptoms FEV 1 Type 2 Inflammation No/less Type 2 Inflammation Earlyonset/allergic Lateonset/eosinophilic Obese Neutrophilic

14 Stepping Up Asthma Treatment 1 Achieve and maintain best possible clinical control 2 Current control Target: Reduction of risk Future risk Symptoms Reliever use Instability / worsened symptoms Exacerbations Activity Lung function Loss of lung function Adverse effects of medications 2a 2b Treatments not requiring specific biomarker criteria Treatments requiring specific biomarker criteria

15 15 Recombinant Humanized Anti-IgE IgG 1 Monoclonal Antibody IgE Omalizumab (Xolair) is the first of a new class of agent that specifically target human IgE; the first biologic approved for treating asthma C 3 region Omalizumab

16 Strunk R & Bloomberg G. N Engl J Med 2006

17 Omalizumab for Asthma in US Inner City Children 419 children, adolescents and adults aged 6-20 years symptoms of persistent asthma or evidence of uncontrolled disease (e.g. hospitalization or unscheduled urgent care within 12 months) one positive skin test for a perennial allergen, weigh kg, and total serum IgE levels between 30 and 1300 kiu/l Dose: mg/kg/ige (kiu/l) q4w Busse WW et al. N Engl J Med 2011

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20 Prevent Fall Asthma Exacerbations by Omalizumab vs ICS Boost 318 Treatment Steps 2 to Treatment Step 5 Treatment Period Teach SJ et al. JACI 2015

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22 Treatment Effects in Relation to Patients with Exacerbation Phenotype

23 Time to First Asthma Exacerbation Eosinophil Count FeNO Periostin Level Hanania NA et al. AJRCCM 2013

24 FeNO Eosinophil Count Periostin Level

25 Benralizumab, a fully human afucosylated mab to IL-5Rα that blocks the effects of IL-5 Mepolizumab (Bosatria) is a humanized murine IgG 1 mab against free IL-5; inhibits binding of IL-5 to IL-5Rα on eos FDA-approved for 12 yrs with severe eos asthma in Nov 2015; 100 mg SC q4w Reslizumab (Cinquil) is a humanized IgG 4 anti-il-5 mab; binds to and neutralizes circulating IL-5 by preventing its binding to eosinophils (given by IV route) Sriaroon P & Ballow M. Clin Rev Allergy Immunol 2016

26 Mepolizumab for Severe Asthma ( DREAM ) 621 patients aged years with a history of recurrent severe asthma exacerbations Eosinophilic inflammation: sputum eos 3%; FeNO 50 ppb; or blood eos 300 cells/ l Taking fluticasone propionate 880 g and additional controller; maintenance oral CS Randomly assigned to IV mepolizumab (75 mg, 250 mg, or 750 mg) or placebo (normal saline) Clinically Significant Exacerbations Pavord ID et al. Lancet 2012

27 Blood Eosinophil Count Sputum Eosinophil Count Prebronchodilator FEV 1 ACQ Score

28 Mepolizumab in Severe Eosinophilic Asthma ( MENSA ) 576 patients aged yrs with asthma and two or more exacerbations in past 12 months Received fluticasone propionate 880 g/day with additional controller FEV 1 < 90% of predicted or FEV 1 /FVC < 0.8 (12-17 yrs) OR FEV 1 < 80% of predicted ( 18 yrs) Blood eos level of 300 cells/μl within the previous year Ortega HG et al. N Engl J Med 2014

29 Asthma Exacerbations P < 0.001

30 FEV 1 P = 0.02 for IV; P = 0.03 for SC

31 Steroid-sparing Effect of Mepolizumab ( SIRIUS ) 135 patients aged 12 yrs (and 45 kg) with asthma 6-mo history of maintenance treatment with systemic glucocorticoids (5 to 35 mg/day of prednisone); all patients received high-dose ICS and an additional controller Blood eos level of 300 cells/μl Bel EH et al. N Engl J Med 2014

32 Change from Baseline in Steroid Dose

33 Asthma Exacerbation

34 Step 1 Step 2 Step 3 Step 4 Step 5 Asthma Education (self monitoring, written action plan, regular review) Treat modifiable factors (tobacco smoke, obesity, anxiety) Advise non-pharmacological strategies (physical activity, weight loss, avoidance of sensitizers) As-needed short-acting 2 -agonist (SABA) As-needed SABA or low-dose ICS/formoterol # Select one Select one Select one Add one or more Add one or both None Low-dose ICS Low-dose ICS plus LABA** Consider low-dose ICS Stepwise Asthma Management Leukotriene receptor antagonist (LTRA) Low-dose theophylline* Medium/high-dose ICS US: plus LABA 12 yrs Refer for add-on treatments: Tiotropium*, omalizumab, or mepolizumab* Medium/high-dose ICS Add tiotropium* Add low-dose oral corticosteroid Low-dose ICS plus LTRA (or theophylline*) EU: 6 yrs; High-dose ICS plus LTRA (or theophylline*) * Not for children < 12 yrs; ** preferred step 3 treatment is medium-dose ICS for children aged 6-11 yrs; # as maintenance and reliever by SMART approach

35 Conclusions Asthma is a major health problem in Asian children The pathogenesis of asthma is heterogeneous (endotypes) Although generally controlled, asthma can be severe and difficult to treat in a small group of children A number of biologics capable of blocking specific endogenous molecules are either approved (omalizumab, mepolizumab) or undergoing clinical trials in asthmatic children who are poorly controlled despite adherence to guideline therapies Only a subset of meticulously selected patients would benefit from biologics, i.e. targeted therapy Offers an opportunity for precision medicine in asthma